Obsessive-Compulsive Disorder (OCD) is a disabling illness that typically begins in adolescence and persists into adulthood. We hypothesize that OCD is due to dysfunction in frontostriatal brain circuits that subserve self-regulatory control processes, and that these disturbances affect stimulus-response 'habit' learning systems within the dorsal striatum and declarative memory systems within medial temporal lobe regions that are components of a mesocorticolimbic reward processing system. In this R21, we will use fMRI to assess the functioning of these three neural systems in 30 unmedicated adults with OCD (ages 18-45) compared to 30 age-matched healthy controls (Primary Aim). The functioning of frontostriatal control systems will be assessed using the well-validated Simon task. The functioning of habit learning and reward processing systems will be assessed using a novel fMRI paradigm directly analogous to tasks used to define the neural bases of learning and memory systems in animal research, tailored to a virtual reality environment within the MRI scanner. This paradigm provides a translational neuroscience approach to the study of brain function in OCD. After scanning, OCD patients will be offered 12 weeks of open treatment with a serotonin reuptake inhibitor (SRI), and we will explore whether our baseline fMRI measures predict SRI response (Secondary Aim). Identification of functional abnormalities (a biosignature) in any of these neural systems in OCD will support future studies to investigate the onset and progression of these brain abnormalities and the effects of treatment. If these abnormalities are associated with treatment response, these fMRI paradigms could become valid biomarkers for OCD. Our long-term goal is to identify a distinct pattern of brain abnormalities that underlies OCD and/or predicts treatment response, and to develop novel treatments that target these abnormalities directly. By validating the use of specific fMRI paradigms to examine potential brain mechanisms underlying OCD, this R21 application is a first step in this direction and consistent with the NIMH strategic plan to promote brain discovery and to identify biomarkers of treatment response.